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Review
. 2014 Dec;35(12):622-630.
doi: 10.1016/j.it.2014.10.003. Epub 2014 Nov 12.

Prion-like polymerization as a signaling mechanism

Xin Cai  1 , Zhijian J Chen  2
Affiliations
Review

Prion-like polymerization as a signaling mechanism

Xin Cai et al. Trends Immunol. 2014 Dec.

Abstract

The innate immune system uses pattern recognition receptors such as RIG-I and NLRP3 to sense pathogen invasion and other danger signals. Activation of these receptors induces robust signal transduction cascades that trigger the production of cytokines important for host protection. MAVS and ASC are essential adaptor proteins downstream of RIG-I and NLRP3, respectively, and both contain N-terminal domains belonging to the death domain superfamily. Recent studies suggest that both MAVS and ASC form functional prion-like fibers through their respective death domains to propagate downstream signaling. Here, we review these findings, and in this context discuss the emerging concept of prion-like polymerization in signal transduction. We further examine the potential benefits of this signaling strategy, including signal amplification, host evolutionary advantage, and molecular memory.

Keywords: pattern recognition receptors; prion-like polymerization; signal transduction; signaling.

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Figures

Figure 1
Figure 1
Model of RIG-I-dependent MAVS activation. Following virus infection, 5′ppp–RNA is generated in the cytoplasm and recognized by RIG-I, bringing multiple RIG-I proteins into proximity and releasing its N-terminal tandem CARDs from autoinhibition. Free RIG-I CARDs can then bind to unanchored K63-linked polyubiquitin, which induces the formation of an active RIG-I tetramer. The active RIG-I tetramer then interacts with the mitochondrial adaptor protein MAVS, through CARD–CARD interactions, and converts MAVS into its prion form. The initial MAVS prion seeds then rapidly convert other native MAVS proteins into the filamentous prion form, eventually leading to the activation of NF-κB and IRF3 for antiviral interferon production. Abbreviations: 5′ppp, 5′ triphosphates; CARD, caspase activation and recruitment domain; K63, lysine 63; NF-κB, nuclear factor-κB; IRF3, interferon regulatory factor 3.
Figure 2
Figure 2
Distinguishing features of MAVS and ASC prion fibers. Cells expressing MAVS or ASC can exist in at least two possible states: a soluble or prion state, which allows a population to take on a bimodal distribution. Unlike microtubule fibers, MAVS or ASC fibers endow heritable states to their host cells. Specifically, when prion fiber-containing cells are serially passaged, a large proportion of the daughter cells will inherit the prion phenotype and the population is again characterized by a bimodal distribution. In sharp contrast to this, when sorted by their average microtubule fiber lengths, cells distribute in one continuous unimodal population, characterized by the relative sizes of their microtubules. Following serial passages, cells initially containing larger microtubule fibers will again produce a unimodal population of cells containing heterogeneous microtubule sizes. Abbreviations: ASC, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; MAVS, mitochondrial antiviral signaling.
Figure 3
Figure 3
Shared and unique features of MAVS and ASC prions. While MAVS and ASC share key properties with other prions (middle box), they also contain unique differences (left and right boxes). Abbreviations: ASC, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; MAVS, mitochondrial antiviral signaling.
Figure 4
Figure 4
Functional prions in immune signaling. In mammals, receptors such as RIG-I and NLRP3 induce the prion conversion of their respective adaptors MAVS and ASC, which then rapidly polymerize leading to protective cytokine secretion and cell death. In filamentous fungi, a homologous pathway depends on the NWD2 protein, which likely converts the downstream HET-S/s protein into a prion to induce cell death. The fungal NWD2/HET-S/s pathway shares remarkable similarities to the mammalian NLRP3/ASC inflammasome in function and organization. Abbreviations: ASC, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; CARD, caspase activation and recruitment domain; CTD, C-terminal domain; LLR, leucine-rich repeat; MAVS, mitochondrial antiviral signalling; NLRP3, NLR family, pyrin domain containing 3; RIG-I, retinoic acid-inducible gene I.
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